A major initiative of NIMH is the early identification of risk intermediate phenotypes (IPs) for psychiatric disorders and the progression of these IPs with recurrence of episodes. The longtime focus on active disease states, rather than the remitted state, has thwarted precise study of these IPs and their stability over time. The present study is designed to better identify neurobiological IPs by enrolling individuals remitted from MDD, early in the course of illness in late adolescence/early adulthood. We will establish the stability of IPs over a three week period, and then follow these individuals for 1 year to use these IPs to predict recurrence of depressive illnesses. Research by our group and others suggests that comorbid depression and anxiety (MDD+A) is a robust subtype for MDD. This supports the previous research that pre-existing anxiety disorder increases risk for MDD, risk for poorer treatment response, and greater chance of relapse. As such, the health benefits of better understanding these young adults has great potential to initiate more tailored treatment strategies, and to identify those most in need of follow-up. Sixty first episode young adults between the ages of 18 and 22 remitted from MDD will be enrolled in the study as well as sixty age and sex matched healthy controls. The MDD subjects will be either remitted from a first episode with positive family history, or between the second and third episodes with no family history. The 70 MDD subjects will be evenly divided between those with and without a prior history of anxiety disorder and compared to 60 healthy control young adults. Neurobiological IP measures include fMRI with emotion, regulation (inhibitory control), and memory paradigms and similar neuropsychological measures (memory, emotion processing, executive functioning). These measures will be used at the index point (remitted state) and again 3 weeks later (to assess trait stability). Analyses will focus on 1) defining the trait MDD+A vs trait MDD IPs, 2) stability of these IPs in the remitted state, and 3) ability of these IPs to predict relapse/recurrence of depressive illness at one year. We will study these individuals at the critical nexus, early in the course of illness where developmental variability will be minimized compared to studies of younger adolescents. This will enable us to assess the presence and stability of these IPs before cumulative illness effects are present. Embedding the search for neurobiological IPs into a relapse prediction study can provide for ready translation of findings into clinical settings. A longitudinal approach solidifies diagnoses, and addresses stability of IP measures, and provides a easy entrie into a clinical application, should our preliminary results from a heterogeneous MDD group be replicated in these more homogeneous samples. The BRAINS mechanism allows this PI to take this innovative, critical venture toward refining his initial work on IPs for adults with MDD+A and MDD. PUBLIC HEALTH RELEVANCE: The early identification of those with risk for depression can result in preventative and/or early treatments, yet intermediate phenotypes of MDD have not been well studied in late adolescence/early adulthood. The present study will identify stable endophenotypes for MDD with and without comorbid anxiety using neurobiological measures that could lead to early identification of those at risk for MDD and facilitate pursuit of risk genes for MDD.